复乳法制备聚乳酸微球及其体外释药性能的测定
|
摘要
为了延长药物对病灶组织的作用时间,提高药物的疗效,可通过对药物结构进行修饰或将药物制成长效缓释制剂。载药微球是将药物溶解或者分散到高分子材料中,形成的微小球状结构。本论文以可生物降解材料聚乳酸(PLA)为载体,水溶性头孢唑啉钠(CEZ)为模型药物,采用复乳法制备了聚乳酸-头孢唑啉钠载药微球;并对微球的包封率、载药量、形貌特征进行了表征;用紫外-可见分光光度法考察了载药微球的体外释药性能。具体结果如下:
1.考察了聚乳酸分子量的大小和体外释药介质对载药微球释药的影响,分别用分子量为10000和25000的聚乳酸制备了载药微球。扫描电镜结果显示微球呈现良好的球形结构,并且表面多孔,对比图片可以看出由分子量较大的聚乳酸制备得到的微球表面空洞较多,这些孔洞为头孢唑啉钠的溶出提供了通道。分子量10000的微球包封率为23.63%,载药量4.27%;分子量25000的微球包封率为34.46%,载药量6%。红外光谱图谱显示微球中有CEZ和PLA两种成分的特征峰。用差热分析法(DTA)分析得知,聚乳酸和模型药物能够有机地结合为一体。紫外分光光度法对不同分子量的载药微球进行体外释药实验,释药介质分别为PBS(pH=7.3)和胃液(pH=1.2),累积释药曲线表明,在同种释药介质中,分子量大的聚乳酸载药微球释放头孢唑啉钠的速度较慢;而相同分子量的载药微球在PBS(pH=7.3)中的释药速度较快。
2.在复乳法的基础上,研究了渗透压在制备微球过程中对微球形貌、包封率、突释效应和释药性能的影响。当内外水相不存在平衡渗透压时,制备的微球具有较高的包封率和载药量,扫描电镜图片显示微球表面光滑无孔;但是随着向内水相加入不同浓度的缓冲溶液时,这时引起了内外水相的渗透压差,导致外水相的水溶液流入内水相,一部分头孢唑啉钠流入外水相;因此制备得到的微球表面多孔,且包封率较低;体外释药曲线显示,表面多空的载药微球具有明显的突释效应,此后是缓慢释放阶段。因此,可以通过改变微球的结构来控制头孢唑啉钠的释放。
In order to prolong the action time of the medicine on lesions tissue and improve the effect of the medicine, the drug can be modified structure or be made to long-acting sustained release preparation. Drug carried microspheres made drug dissolve or disperse into polymer materials, forming microspherical structure. In this thesis, polylactic acid-microspheres containing cefamezin were prepared by a W/O/W multiple emulsion solvent evaporation method. The resulted microspheres were characterized with respect to encapsulation efficiency, drug loading, and morphological characteristics. The drug releasing properties of microspheres in vitro were researched by UV-Vis absorption spectrophotometric methods.
1. The effects of molecular weight of PLA and drug release medium on the drug-releasing performance of the PLA microspheres were investigated. PLA-CEZ microspheres were prepared by using molecular weight of 10000 and 25000 of polylactic acid. SEM images indicated that the micropheres had a porous structure, and PLA-CEZ microspheres prepared by high molecular weight of PLA were porous, which provided channels of the CEZ from PLA-CEZ. The encapsulation efficiencies were 23.63% and 34.46%, the drug loading were 4.27% and 6%, respectively. It was proved that PLA-CEZ contained the characteristic peaks of cefamezin and polylactic acid by FT-IR. The thermal behavior by differential thermal analysis indicated cefamezin and PLA mingled each other. The releasing behavior of microspheres prepared by different molecular weight of PLA was studied by UV-Vis in PBS and gastric juice. The cumulative release demonstrated that PLA-CEZ prepared by high molecular weight of PLA had a slow-release behavior in the same drug release medium, PLA-CEZ prepared by the same molecular weight of PLA release more quickly in PBS.
2. Based on W/O/W multiple emulsion, the effect of osmotic pressure difference between inner water phase and outer water phase on morphological characteristics encapsulation efficiency, burst release and the drug releasing property was studied. When there is no osmotic pressure difference between inner phase and outer phase, the microspheres were smooth and compact with few pores, high encapsulation efficiency and drug loading. Different concentrations of buffer solution addition to the internal aqueous phase create the different osmotic pressure between the inner and outer water phase. Because of osmotic pressure, CEZ was lost into the outer water phase resulted from influx of water from the outer phas, the microspheres was more pores and encapsulation efficiency was low. The drug release from microspheres having many pores on its surface consisted of burst release phase followde by a slow release phase. The CEZ release from the micropheres could be controlled through changes in the structure of the microspheres.
1.考察了聚乳酸分子量的大小和体外释药介质对载药微球释药的影响,分别用分子量为10000和25000的聚乳酸制备了载药微球。扫描电镜结果显示微球呈现良好的球形结构,并且表面多孔,对比图片可以看出由分子量较大的聚乳酸制备得到的微球表面空洞较多,这些孔洞为头孢唑啉钠的溶出提供了通道。分子量10000的微球包封率为23.63%,载药量4.27%;分子量25000的微球包封率为34.46%,载药量6%。红外光谱图谱显示微球中有CEZ和PLA两种成分的特征峰。用差热分析法(DTA)分析得知,聚乳酸和模型药物能够有机地结合为一体。紫外分光光度法对不同分子量的载药微球进行体外释药实验,释药介质分别为PBS(pH=7.3)和胃液(pH=1.2),累积释药曲线表明,在同种释药介质中,分子量大的聚乳酸载药微球释放头孢唑啉钠的速度较慢;而相同分子量的载药微球在PBS(pH=7.3)中的释药速度较快。
2.在复乳法的基础上,研究了渗透压在制备微球过程中对微球形貌、包封率、突释效应和释药性能的影响。当内外水相不存在平衡渗透压时,制备的微球具有较高的包封率和载药量,扫描电镜图片显示微球表面光滑无孔;但是随着向内水相加入不同浓度的缓冲溶液时,这时引起了内外水相的渗透压差,导致外水相的水溶液流入内水相,一部分头孢唑啉钠流入外水相;因此制备得到的微球表面多孔,且包封率较低;体外释药曲线显示,表面多空的载药微球具有明显的突释效应,此后是缓慢释放阶段。因此,可以通过改变微球的结构来控制头孢唑啉钠的释放。
In order to prolong the action time of the medicine on lesions tissue and improve the effect of the medicine, the drug can be modified structure or be made to long-acting sustained release preparation. Drug carried microspheres made drug dissolve or disperse into polymer materials, forming microspherical structure. In this thesis, polylactic acid-microspheres containing cefamezin were prepared by a W/O/W multiple emulsion solvent evaporation method. The resulted microspheres were characterized with respect to encapsulation efficiency, drug loading, and morphological characteristics. The drug releasing properties of microspheres in vitro were researched by UV-Vis absorption spectrophotometric methods.
1. The effects of molecular weight of PLA and drug release medium on the drug-releasing performance of the PLA microspheres were investigated. PLA-CEZ microspheres were prepared by using molecular weight of 10000 and 25000 of polylactic acid. SEM images indicated that the micropheres had a porous structure, and PLA-CEZ microspheres prepared by high molecular weight of PLA were porous, which provided channels of the CEZ from PLA-CEZ. The encapsulation efficiencies were 23.63% and 34.46%, the drug loading were 4.27% and 6%, respectively. It was proved that PLA-CEZ contained the characteristic peaks of cefamezin and polylactic acid by FT-IR. The thermal behavior by differential thermal analysis indicated cefamezin and PLA mingled each other. The releasing behavior of microspheres prepared by different molecular weight of PLA was studied by UV-Vis in PBS and gastric juice. The cumulative release demonstrated that PLA-CEZ prepared by high molecular weight of PLA had a slow-release behavior in the same drug release medium, PLA-CEZ prepared by the same molecular weight of PLA release more quickly in PBS.
2. Based on W/O/W multiple emulsion, the effect of osmotic pressure difference between inner water phase and outer water phase on morphological characteristics encapsulation efficiency, burst release and the drug releasing property was studied. When there is no osmotic pressure difference between inner phase and outer phase, the microspheres were smooth and compact with few pores, high encapsulation efficiency and drug loading. Different concentrations of buffer solution addition to the internal aqueous phase create the different osmotic pressure between the inner and outer water phase. Because of osmotic pressure, CEZ was lost into the outer water phase resulted from influx of water from the outer phas, the microspheres was more pores and encapsulation efficiency was low. The drug release from microspheres having many pores on its surface consisted of burst release phase followde by a slow release phase. The CEZ release from the micropheres could be controlled through changes in the structure of the microspheres.
引文
[1]戈进杰.生物降解高分子材料及其应用[M].北京:化学工业出版社,2002,9.
[2]李宝玉.生物医学材料[M].北京:化学工业出版社,2003,9.
[3]刘盛辉,郎美东.新一代生物医用材料[J].高分子通报,2005,6:113-117.
[4]Larry L H,Julia M P.Third-generation biomedical materials[J].Science,2002,295:1014-1017.
[5]Nicholas A P,Robert L.New challenges inbiomaterials[J].Science,1994,263:1715-1720.
[6]晨爱民,万涛.生物医学材料研究与展望[J].武汉理工大学学报,2005,27(8):116-118.
[7]Rosenberg A,Gr(a|¨)tz K W,Sailer H F.Should titanium miniplates be removed after bone healing is complete[J].International Journal of Oral and Maxillofacial Surgery,1993,22(3):185-188.
[8]Sittinger M,Bujiat J,Rotter N,et al.Tissue engineering and autologous transplant formation:practical approaches with resorbable biomaterials and new cell Culture techniques[J].Biomaterials,1996,17(3):237-242.
[9]Sabolinski M L,Alvarez O,Auletta M,et al.Cultured skin as a"smart material" for healing wounds:experience in venous ulcers[J].Biomaterials,1996,17(3):311-320.
[10]陆声,林月秋,常山.生物活性材料的设计及研究进展[J].国外医学生物医学工程分册,2001,24(3):138-141.
[11]Kim B S,David J M.Development of biocompatible synthetic extracellular matrices for tissue engineering[J].Trends Biotechnol,1998,16(5):224-230.
[12]David J M,Joseph P V.Tissue engineering using cells and synthetic polymers[J].Transplantation Reviews,1993,7:153-162.
[13]Rahul S,Kumar A,Lopez G P.Engineering Cell Shapeand Funetion[J].Science,1994,264:696-698.
[14]余耀庭,张兴栋.生物医用材料[M].天津:天津大学出版社
[15]Song C X,Labhasetwar V,Murphy H,et al.Formulation and characterization of biodegradable nano particles for intravascular local drug delivery[J].J Control Rel,1997,43:197-212.
[16]Maulding H V.Prolonged delivery of peptides by microeapsules[J].Journal of Controlled Release,1987,6(1):167-176.
[17]Inmaculada M,Suming L,Manuel B M,et al.Protein release from physically erosslinked hydrogels of the PLA/PEO/PLA tribloek copolymer-type[J].Biomaterials,2001,22(8):363-369.
[18]Damge C,Miehele C,Aprahanian M,et al.New approach for oral administration of insulin with polyalkyl eyanoacrylate nano partieals as drug carrier[J].Diabetes,1998,37:246.
[19]Akira T,Ikumi T.Carder-mediated or specialized transport of drugs across the blood-brain barrier[J].Advanced Drug Delivery Reviews,1999,36:277-290.
[20]Go(?)N,Fritz H,Maier M,et al.Effects of oligonueleotide adsorption on the physieochemieal characteristics of a nanopartiele-based model delivery system for antisense drugs[J].Colloid Polym Sci,1999,277:145-152.
[21]刘凤兴,程为庄.生物可降解高分子材料及其在药物释放中的应用[J].高分子通报,2005,6:38-41.
[22]王华杰,刘新铭,王瑾哗.天然高分子药物微球载体材料的研究进展[J].高分子通报,2006,8:1-8.
[23]吕泽,王身国.高分子包囊药物释放体系[J].功能高分子学报,1997,10(3):429-434.
[24]Ignatius A A.,Claes L X.In vitro biocompatibility of bioresorbable polymers:poly(L,DL-lactide)and poly(L-lactide-eo-glyeolide)[J].Biomaterials,1996,17(8):831-839.
[25]高钊,涂春,玲王征.聚酸酐共聚物在药物缓控释领域中的研究进展[J].高分子通报,2006,7:10-16.
[26]Hoste K,Schacht E,Seymour L.New derivatives of polyglutarnic acid as drug carrier systems[J].Journal of Controlled Release,2000,64:53-61.
[27]李孝红,袁明龙,熊成东等.聚乳酸及其共聚物的合成和在生物医学上的应用[J].高分子通报,1999,1:24-30.
[28]刘芳,贾德民.聚乳酸及其复合材料在骨组织工程方面的研究进展[J].生物医学工程学杂志,2001,18(3):448-450。
[29]曹雪波,王远亮,潘君等。马来酸酐改性聚乳酸的力学性能研究[J].高分子材料科学与工程,2002,18(1):115-118.
[30]Witschi C,Doelker E.Influence of the microeneapsulation method and peptide loading on poly(lactic acid)and poly(lactie-eo-glycolie acid)degradation during in vitro testing[J].Journal of Controlled Release,1998,51(223):327-341.
[31]朱振峰,杨菁.药物纳米控释系统的最新研究进展[J].国外医学生物医学工程分册,1998,6:327-332.
[32]朱明华,蒋丽.高分子材料的降解及腐蚀机理[J].国外医学生物医学工程分册,1996,19(6):343-346
[33]何应,魏树礼.聚乳酸微球的体外降解[J].北京大学学报(医学版),2001,33(4):358-361.
[34]Huo D J,Deng S H,Li L B,et al.Studies on the poly(lactic-eo-glyeolie)acid mierospheres of cisplatin for lung-targeting[J].International Journal of Pharmaceuties,2005,289(122):63-67.
[35]Urata T,Arimori K,Nakano H.Modification of release rates of cyelosporin A from polyl (L-lactic acid)microspheres byfatty acid esters and in-vivo evaluation of the mierospheres [J].Journal of Controlled Release,1999,58(2):133-141.
[36]Bergsma J E.,de Bruijn W C,Rozema F R,et al.Late degradation tissue response to poly(L-lactide)bone plates and serews[J].Biomaterials,1995,16(1):25-31.
[37]Pitt C G,Gratzel M M,Kimmel G L,et al.Aliphatic polyesters:Ⅱ.The degradation of poly (DL-lactide),poly(caprolactone)and theircopolymers in vivo[J].Biomaterials,1981,2:215-220.
[38]Ibrahim M A,Ismall A,Fetouh M I,et al.Stability of insulin during the erosion of poly(lactie acid)and poly(lactic-eo-glycolic acid)mierospheres[J].Journal of Controlled Release,2005,106(3):241-252.
[39]Yasuyosi M,Kazuyuki J,Masahito O,et al.Preparation and properties of biodegradable copoly(N-hydroxyalkyl-D,L-glutamine)membranes[J].European Polymer Journal,1999,35(5):767-773.
[40]张瑶.缓释微球制剂的研究进展[J].医药导报,2004,23(11):843-844.
[41]曹婷颖,顾月清,高向东.聚乳酸载药微球的制备和给药方法[J].药学进展,2006,30(10):448-452.
[42]赵耀明,汪朝阳,麦杭珍等.聚乳酸的直接合成及其红霉素肺靶向药物微球的应用[J].高分子材料科学与工程,2003,19(5):145-148.
[43]Carballido A,Vanrell R,Martinez I T,et al.Biodegradable ibuprofen-ioaded PLGA mierospheres for intraartieular admin-istration.Effect of Labrafil addition on release in vitro [J].International Journal of Pharrnaceutics,2004,279(1-2):33-41.
[44]任杰,宋金星.聚乳酸及其共聚物在缓释药物中的研究及应用[J].同济大学学报,2003,31(9):1054-1058.
[45]郭健新,王荣.以聚乳酸为聚合物材料制备微粒给药系统[J].药学进展,1996,20(3):135-138.
[46]李雄伟,肖锦,李晓毅等.微米级可生物降解高分子微球的制备研究[J].高分子材料科学与工程,1998,14(3):20-22.
[47]李德冠,姜丹,姜云垒等.聚乳酸微球的制备[J].吉林大学学报(理学版),2005,43(6):842-846
[48]廖戎.聚乳酸微球制备的初步研究[J].西南民族大学学报.自然科学版,2006,32(1):84-87
[49]洪波,王宝国.微孔分散法制备单分散微胶囊研究进展[J].高分子通报,2005,3:33-39.
[50]Chung T W,Huang Y Y,Liu Y Z.Effects of the rate of solvent evaporation on the characteristics of drug loaded PLLA and PDLLA mierospheres[J].International Journal of Pharmaceuties,2001,212(2):161-169.
[51]Roland B,Omlaksana P.Drug release from laminated polymeric films prepared from aqueous latexes[J].Journal of Pharmaceutical Sciences,1990,79(1):32-36.
[52]Zambaux M F,Bonneaux F,Gref R,et al.Irfluenee of experimental parameters on the characteristics of poly(lactie acid)nanoparticles prepared by a double emulsion method.Journal of Controlled Release,1998,50:31-40.
[53]Carrasguillo K G,Stanley A M,Aponte-Carro J C,et al.Non-aqueous encapsulation of excipient-stabilized spray-freeze dried BSA into poly(lactide-co-glycolide) microspheres results in release of native protein[J]. Journal of Controlled Release, 2001 ,76(3): 199-208.
[1]Kumaresh S S,Tejraj M A,Anandrao R K,et al.Biodegradable polymeric nanoparticles as drug delivery devices[J].Journal of Controlled Release,2001,70:1-20.
[2]Niwa T,Takeuchi H,Hino T,et al.Biodegradable submieron carriers for peptide drugs:Preparation of DL-lactide/glycolide copolymer(PLGA)nanospheres with nafarelin acetate by a novel emulsion-phase separation method in an oil system[J].International Journal of Pharmaceutics,1995,121:45-54.
[3]Takahashi M,Onishi H,Machida Y.Development of implant tablet for a week-long sustained release[J].Journal of Controlled Release,2004,100:63-74.
[4]白雁斌,黄晓琴,雷自强.聚乳酸类医用生物降解材料的研究进展[J].高分子通报,2006,3:46-51.
[5]王晶,王勤,李静.聚乳酸微球制剂的研究概况[J].山东生物医学工程,1999,18(3):50-53.
[6]Park S J,Kim S H Preparation and characterization of biodegradable poly(1-lactide)/poly(ethylene glycol)microcapsules containing erythromycin by emulsion solvent evaporation technique[J].Journal of Colloid and Interface Science,2004,271:336-341.
[7]杨艳红,郝永梅,赵凤林等.非离子表面活性剂囊泡包封药物头孢唑啉钠的研究[J].化学通报,2002,7:467-471.
[8]Kathleen J P,Martinus J D,Kathy F,et al.In vitro and in vivo degradation of double-walled polymer mierospheres[J].Journal of Controlled Release,1996,40:169-178.
[9]He Y,Wei S 1.Study on the Degradation of Polylactide Microsphere In Vitro[J].Journal of Chinese Pharmaceutical Sciences,2001,10(1):20-23.
[10]Sansdrap P,Moe"s A J.In vitro evaluation of the hydrolytic degradation of dispersed and aggregated poly(DL-lactide-eo-glycolide)microspheres[J].Journal of Controlled Release,1997,43:47-58.
[11]Jin W L,Feng J H,Doo S L.Thermoreversible gelation of biodegradable poly(ε-eaprolaetone)and poly(ethylene glycol)multibloek copolymers in aqueous solutions[J].Journal of Controlled Release,2001,73:315-327
[12]程青,卢文庆,聂素云.硫酸庆大霉素聚乳酸微球的制备及其体外缓释度的测定[J].南京师大学报(自然科学版),2006,29(2):55-58.
[13]黄开红,朱兆华,刘建化等.聚乳酸载药纳米微粒制备及其释药性能[J].癌症,2005,24(8):1023-1028.
[14]兰婷,郝红,赵君民.聚乳酸载药微球制备及释药性能研究最新进展[J].离子交换与吸附,2006,22(5):475-480.
[15]Calieeti P,Salmaso S,Elvassore N.Effective protein release from PEG/PLA nano-partieles produced by compressed gas anti-solvent precipitation techniques[J].Journal of Controlled Release,2004,94:195-205.
[16]Conway B R,Eyles J E,Alpar H O.A comparative study on the immune responses to antigens in PLA and PHB mierospheres[J].Journal of Controlled Release,1997,49:1-9.
[17]李良,李国明,黎茂荣.聚乳酸载利福平微球的制备及其释药性能[J].应用化学,2003,20(1):65-68.
[18]杨帆,陈一月,林茵等.聚乳酸的降解性能及其微球剂的研究[J].中国药房,2002,13(5):263-265.
[19]Zhou S B,Liao X Y,Li X H,et al.Poly-D,L-lactide-co-poly(ethylene glycol)mierospheres aspotential vaccine delivery systems[J].Journal of Controlled Release,2003,86:195-205.
[20]Siepmarm J,Faisant N,Akiki J.Effect of the size of biodegradable mieropartieles on drug release:experiment and theory[J].Journal of Controlled Release,2004,96:123-134.
[21]Jonnalagadda S,Robinson D H.Effect of the Inclusion of PEG on the Solid-State Properties and Drug Release from Polylaetie Acid Films and Mieroeapsules[J].Journal of Applied Polymer Science,2004,93:2025-2030.
[22]Park T G.Degradation of poly(D,L-laetic acid)microspheres:effect of molecular weight[J].Journal of Controlled Release,1994,30(2):161-173.
[1]丁立,张钧寿,龚明涛等.W/O/W型复乳剂的稳定性、生物分布和体外释放[J].药学进展,2000,1:12-16.
[2]汪自然,徐启勇,叶燕青.复乳法制备聚乳酸及其共聚物微球参数的研究进展[J].国际生物医学工程杂志,2006,29(4):238-242.
[3]Hart K,Lee K D,Gao Z G,et al.Preparation and evaluation of poly(L-lactic acid)microspherescontaining rhEGF for chronic gastric ulcer healing[J].Journal of Controlled Release,2001,75(3):259-269.
[4]Herrmann J,Bodmeier R.Somatostatin containing biodegradable microspheres prepared by a modified solvent evaporation method based on W/O/W-multiple emulsions[J].International Journal of Pharmaceutics,1995,126:129-138.
[5]Crotts G,Park T G.Preparation of porous and nonporous biodegradable polymeric hollow microspheres[J].Journal of Controlled Release,1995,35(2-3):91-105.
[6]Geiger S,Tokgoz S,Fructus A,et al.Kinetics of swelling-breakdown of a W/O/W multiple emulsion:possible mechanisms for the lipophilic surfactant effect[J].Journal of Controlled Release,1998,52(1-2):99-107.
[7]Yang Y Y,Chia H H,Chung T S.Effect of preparation temperature on the characteristics and release profiles of PLGA microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation[J].Journal of Controlled Release,2000,69(1):81-96.
[8]张建军,高缘,平其能.复乳化法制备聚乳酸微球的动态过程及其物理参数研究[J].中国药学杂志,2005,40(6):441-444.
[9]宋薇,马光辉,苏志国.复乳法制备大孔聚合物微球[J].过程工程学报,2007,7(5):1029-103.
[10]谭红香,叶建东.PLGA包埋硫酸庆大霉素缓释微球的制备及体外释放行[J].中国抗生素杂志,2007,32(11):682-684.
[11]Erden N,Celebi N.Factors influencing release of salbutamol sulphate from poly(lactide-co-glycolide)microspheres prepared by water-in-oil-in-water emulsion technique[J].International Journal of Pharmaceutics,1996,137(1):57-66.
[12]Yang Y Y,Chung T S,Bai X L,et al.Effect of preparation conditions on morphology and release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion method[J].Chemical Engineering Science,2000,5:2223-2236.
[13]Meng F T,Ma(3 H,Qiu W.W/O/W Double Emulsion Technique Using Ethyl Acetate as Organic Solvent:Effect of Its Diffusion Rate on the Characterization of Microparticles[J].Journal of Controlled Release,2003,91:407-416.
[14]Florence A T,Whitehill D.Some Features of Breakdown in Water-in-oil-in-water Multiple Emulsions[J].Journal Colloid Interface Sci.,1981,79:243-256.
[15]Sah H K,Toddywala R,Chien Y W.The influence of biodegradable microcapsule formulations on the controlled release of a protein[J].Journal of Controlled Release,1994,30:201-211.
[16]Herrmann J,Bodmeier R.The effect of particle microstructure on the somatostatin release from poly(lactide)microspheres prepared by a W/O/W solvent evaporation method[J].Journal of Controlled Release,1995,36(1-2):63-71.
[17]Ghadefi R,Sturesson C,Carlfors J.Effect of preparative parameters on the (D,L-lactide-co-glycolide)microspheres emulsion method characteristics of polymade by the double[J].International Journal of Pharmaceutics,1996,141(1-2):205-216.
[18]Ruana G,Feng S S,Li Q T.Effects of material hydrophobicity on physical properties of polymeric microspheres formed by double emulsion process[J].Journal of Controlled Release,2002,84(3):151-160.
[19]Ruana G,Feng S S.Preparation and characterization of poly(lactic acid)-poi(ethyleneglycol)-poly(lactic acid)(PLA-PEG-PLA)microspheres for controlled release of paclitaxel[J].Biomaterials,2003,24(27):5037-5044.
[20]王峰,涂家生,张钧寿,等.PLGA微球控释系统的突释及其控制[J].药学进展,2003,27(3):142-146.
[21]Wang J,Wang B M,Schwendeman S P.Characterization of the initial burst release of a model poptide from POly(d,l-lae-tide-co-glycofide)microspheres[J].Journal of Controlled Release,2002,82(2-3):289-307.
[22]Takenaga M,Yarnaguchi Y,Kitagawa A,et al.A novel sus-tained-release formulation of insulin with dramatic reduction in initial rapid release[J].Journal of Controlled Release,2002,79(1-3):81-91.
[23]Makoto M,Akiko K,Jun'ichi O,et al.Mechanism of drug release from poly(L-lactic acid)matrix containing acidic or neutral drugs[J].Journal of Controlled Release,1999,60(1-2):199-209.
[24]Urata T,Arimori K,Nakano M.Modification of release rates of eyelosporin A from polyl(L-laetic acid)mierospheres by fatty acid esters and in-vivo evaluation of the microspheres[J].Journal of Controlled Release,1999,58(2):133-141.
[2]李宝玉.生物医学材料[M].北京:化学工业出版社,2003,9.
[3]刘盛辉,郎美东.新一代生物医用材料[J].高分子通报,2005,6:113-117.
[4]Larry L H,Julia M P.Third-generation biomedical materials[J].Science,2002,295:1014-1017.
[5]Nicholas A P,Robert L.New challenges inbiomaterials[J].Science,1994,263:1715-1720.
[6]晨爱民,万涛.生物医学材料研究与展望[J].武汉理工大学学报,2005,27(8):116-118.
[7]Rosenberg A,Gr(a|¨)tz K W,Sailer H F.Should titanium miniplates be removed after bone healing is complete[J].International Journal of Oral and Maxillofacial Surgery,1993,22(3):185-188.
[8]Sittinger M,Bujiat J,Rotter N,et al.Tissue engineering and autologous transplant formation:practical approaches with resorbable biomaterials and new cell Culture techniques[J].Biomaterials,1996,17(3):237-242.
[9]Sabolinski M L,Alvarez O,Auletta M,et al.Cultured skin as a"smart material" for healing wounds:experience in venous ulcers[J].Biomaterials,1996,17(3):311-320.
[10]陆声,林月秋,常山.生物活性材料的设计及研究进展[J].国外医学生物医学工程分册,2001,24(3):138-141.
[11]Kim B S,David J M.Development of biocompatible synthetic extracellular matrices for tissue engineering[J].Trends Biotechnol,1998,16(5):224-230.
[12]David J M,Joseph P V.Tissue engineering using cells and synthetic polymers[J].Transplantation Reviews,1993,7:153-162.
[13]Rahul S,Kumar A,Lopez G P.Engineering Cell Shapeand Funetion[J].Science,1994,264:696-698.
[14]余耀庭,张兴栋.生物医用材料[M].天津:天津大学出版社
[15]Song C X,Labhasetwar V,Murphy H,et al.Formulation and characterization of biodegradable nano particles for intravascular local drug delivery[J].J Control Rel,1997,43:197-212.
[16]Maulding H V.Prolonged delivery of peptides by microeapsules[J].Journal of Controlled Release,1987,6(1):167-176.
[17]Inmaculada M,Suming L,Manuel B M,et al.Protein release from physically erosslinked hydrogels of the PLA/PEO/PLA tribloek copolymer-type[J].Biomaterials,2001,22(8):363-369.
[18]Damge C,Miehele C,Aprahanian M,et al.New approach for oral administration of insulin with polyalkyl eyanoacrylate nano partieals as drug carrier[J].Diabetes,1998,37:246.
[19]Akira T,Ikumi T.Carder-mediated or specialized transport of drugs across the blood-brain barrier[J].Advanced Drug Delivery Reviews,1999,36:277-290.
[20]Go(?)N,Fritz H,Maier M,et al.Effects of oligonueleotide adsorption on the physieochemieal characteristics of a nanopartiele-based model delivery system for antisense drugs[J].Colloid Polym Sci,1999,277:145-152.
[21]刘凤兴,程为庄.生物可降解高分子材料及其在药物释放中的应用[J].高分子通报,2005,6:38-41.
[22]王华杰,刘新铭,王瑾哗.天然高分子药物微球载体材料的研究进展[J].高分子通报,2006,8:1-8.
[23]吕泽,王身国.高分子包囊药物释放体系[J].功能高分子学报,1997,10(3):429-434.
[24]Ignatius A A.,Claes L X.In vitro biocompatibility of bioresorbable polymers:poly(L,DL-lactide)and poly(L-lactide-eo-glyeolide)[J].Biomaterials,1996,17(8):831-839.
[25]高钊,涂春,玲王征.聚酸酐共聚物在药物缓控释领域中的研究进展[J].高分子通报,2006,7:10-16.
[26]Hoste K,Schacht E,Seymour L.New derivatives of polyglutarnic acid as drug carrier systems[J].Journal of Controlled Release,2000,64:53-61.
[27]李孝红,袁明龙,熊成东等.聚乳酸及其共聚物的合成和在生物医学上的应用[J].高分子通报,1999,1:24-30.
[28]刘芳,贾德民.聚乳酸及其复合材料在骨组织工程方面的研究进展[J].生物医学工程学杂志,2001,18(3):448-450。
[29]曹雪波,王远亮,潘君等。马来酸酐改性聚乳酸的力学性能研究[J].高分子材料科学与工程,2002,18(1):115-118.
[30]Witschi C,Doelker E.Influence of the microeneapsulation method and peptide loading on poly(lactic acid)and poly(lactie-eo-glycolie acid)degradation during in vitro testing[J].Journal of Controlled Release,1998,51(223):327-341.
[31]朱振峰,杨菁.药物纳米控释系统的最新研究进展[J].国外医学生物医学工程分册,1998,6:327-332.
[32]朱明华,蒋丽.高分子材料的降解及腐蚀机理[J].国外医学生物医学工程分册,1996,19(6):343-346
[33]何应,魏树礼.聚乳酸微球的体外降解[J].北京大学学报(医学版),2001,33(4):358-361.
[34]Huo D J,Deng S H,Li L B,et al.Studies on the poly(lactic-eo-glyeolie)acid mierospheres of cisplatin for lung-targeting[J].International Journal of Pharmaceuties,2005,289(122):63-67.
[35]Urata T,Arimori K,Nakano H.Modification of release rates of cyelosporin A from polyl (L-lactic acid)microspheres byfatty acid esters and in-vivo evaluation of the mierospheres [J].Journal of Controlled Release,1999,58(2):133-141.
[36]Bergsma J E.,de Bruijn W C,Rozema F R,et al.Late degradation tissue response to poly(L-lactide)bone plates and serews[J].Biomaterials,1995,16(1):25-31.
[37]Pitt C G,Gratzel M M,Kimmel G L,et al.Aliphatic polyesters:Ⅱ.The degradation of poly (DL-lactide),poly(caprolactone)and theircopolymers in vivo[J].Biomaterials,1981,2:215-220.
[38]Ibrahim M A,Ismall A,Fetouh M I,et al.Stability of insulin during the erosion of poly(lactie acid)and poly(lactic-eo-glycolic acid)mierospheres[J].Journal of Controlled Release,2005,106(3):241-252.
[39]Yasuyosi M,Kazuyuki J,Masahito O,et al.Preparation and properties of biodegradable copoly(N-hydroxyalkyl-D,L-glutamine)membranes[J].European Polymer Journal,1999,35(5):767-773.
[40]张瑶.缓释微球制剂的研究进展[J].医药导报,2004,23(11):843-844.
[41]曹婷颖,顾月清,高向东.聚乳酸载药微球的制备和给药方法[J].药学进展,2006,30(10):448-452.
[42]赵耀明,汪朝阳,麦杭珍等.聚乳酸的直接合成及其红霉素肺靶向药物微球的应用[J].高分子材料科学与工程,2003,19(5):145-148.
[43]Carballido A,Vanrell R,Martinez I T,et al.Biodegradable ibuprofen-ioaded PLGA mierospheres for intraartieular admin-istration.Effect of Labrafil addition on release in vitro [J].International Journal of Pharrnaceutics,2004,279(1-2):33-41.
[44]任杰,宋金星.聚乳酸及其共聚物在缓释药物中的研究及应用[J].同济大学学报,2003,31(9):1054-1058.
[45]郭健新,王荣.以聚乳酸为聚合物材料制备微粒给药系统[J].药学进展,1996,20(3):135-138.
[46]李雄伟,肖锦,李晓毅等.微米级可生物降解高分子微球的制备研究[J].高分子材料科学与工程,1998,14(3):20-22.
[47]李德冠,姜丹,姜云垒等.聚乳酸微球的制备[J].吉林大学学报(理学版),2005,43(6):842-846
[48]廖戎.聚乳酸微球制备的初步研究[J].西南民族大学学报.自然科学版,2006,32(1):84-87
[49]洪波,王宝国.微孔分散法制备单分散微胶囊研究进展[J].高分子通报,2005,3:33-39.
[50]Chung T W,Huang Y Y,Liu Y Z.Effects of the rate of solvent evaporation on the characteristics of drug loaded PLLA and PDLLA mierospheres[J].International Journal of Pharmaceuties,2001,212(2):161-169.
[51]Roland B,Omlaksana P.Drug release from laminated polymeric films prepared from aqueous latexes[J].Journal of Pharmaceutical Sciences,1990,79(1):32-36.
[52]Zambaux M F,Bonneaux F,Gref R,et al.Irfluenee of experimental parameters on the characteristics of poly(lactie acid)nanoparticles prepared by a double emulsion method.Journal of Controlled Release,1998,50:31-40.
[53]Carrasguillo K G,Stanley A M,Aponte-Carro J C,et al.Non-aqueous encapsulation of excipient-stabilized spray-freeze dried BSA into poly(lactide-co-glycolide) microspheres results in release of native protein[J]. Journal of Controlled Release, 2001 ,76(3): 199-208.
[1]Kumaresh S S,Tejraj M A,Anandrao R K,et al.Biodegradable polymeric nanoparticles as drug delivery devices[J].Journal of Controlled Release,2001,70:1-20.
[2]Niwa T,Takeuchi H,Hino T,et al.Biodegradable submieron carriers for peptide drugs:Preparation of DL-lactide/glycolide copolymer(PLGA)nanospheres with nafarelin acetate by a novel emulsion-phase separation method in an oil system[J].International Journal of Pharmaceutics,1995,121:45-54.
[3]Takahashi M,Onishi H,Machida Y.Development of implant tablet for a week-long sustained release[J].Journal of Controlled Release,2004,100:63-74.
[4]白雁斌,黄晓琴,雷自强.聚乳酸类医用生物降解材料的研究进展[J].高分子通报,2006,3:46-51.
[5]王晶,王勤,李静.聚乳酸微球制剂的研究概况[J].山东生物医学工程,1999,18(3):50-53.
[6]Park S J,Kim S H Preparation and characterization of biodegradable poly(1-lactide)/poly(ethylene glycol)microcapsules containing erythromycin by emulsion solvent evaporation technique[J].Journal of Colloid and Interface Science,2004,271:336-341.
[7]杨艳红,郝永梅,赵凤林等.非离子表面活性剂囊泡包封药物头孢唑啉钠的研究[J].化学通报,2002,7:467-471.
[8]Kathleen J P,Martinus J D,Kathy F,et al.In vitro and in vivo degradation of double-walled polymer mierospheres[J].Journal of Controlled Release,1996,40:169-178.
[9]He Y,Wei S 1.Study on the Degradation of Polylactide Microsphere In Vitro[J].Journal of Chinese Pharmaceutical Sciences,2001,10(1):20-23.
[10]Sansdrap P,Moe"s A J.In vitro evaluation of the hydrolytic degradation of dispersed and aggregated poly(DL-lactide-eo-glycolide)microspheres[J].Journal of Controlled Release,1997,43:47-58.
[11]Jin W L,Feng J H,Doo S L.Thermoreversible gelation of biodegradable poly(ε-eaprolaetone)and poly(ethylene glycol)multibloek copolymers in aqueous solutions[J].Journal of Controlled Release,2001,73:315-327
[12]程青,卢文庆,聂素云.硫酸庆大霉素聚乳酸微球的制备及其体外缓释度的测定[J].南京师大学报(自然科学版),2006,29(2):55-58.
[13]黄开红,朱兆华,刘建化等.聚乳酸载药纳米微粒制备及其释药性能[J].癌症,2005,24(8):1023-1028.
[14]兰婷,郝红,赵君民.聚乳酸载药微球制备及释药性能研究最新进展[J].离子交换与吸附,2006,22(5):475-480.
[15]Calieeti P,Salmaso S,Elvassore N.Effective protein release from PEG/PLA nano-partieles produced by compressed gas anti-solvent precipitation techniques[J].Journal of Controlled Release,2004,94:195-205.
[16]Conway B R,Eyles J E,Alpar H O.A comparative study on the immune responses to antigens in PLA and PHB mierospheres[J].Journal of Controlled Release,1997,49:1-9.
[17]李良,李国明,黎茂荣.聚乳酸载利福平微球的制备及其释药性能[J].应用化学,2003,20(1):65-68.
[18]杨帆,陈一月,林茵等.聚乳酸的降解性能及其微球剂的研究[J].中国药房,2002,13(5):263-265.
[19]Zhou S B,Liao X Y,Li X H,et al.Poly-D,L-lactide-co-poly(ethylene glycol)mierospheres aspotential vaccine delivery systems[J].Journal of Controlled Release,2003,86:195-205.
[20]Siepmarm J,Faisant N,Akiki J.Effect of the size of biodegradable mieropartieles on drug release:experiment and theory[J].Journal of Controlled Release,2004,96:123-134.
[21]Jonnalagadda S,Robinson D H.Effect of the Inclusion of PEG on the Solid-State Properties and Drug Release from Polylaetie Acid Films and Mieroeapsules[J].Journal of Applied Polymer Science,2004,93:2025-2030.
[22]Park T G.Degradation of poly(D,L-laetic acid)microspheres:effect of molecular weight[J].Journal of Controlled Release,1994,30(2):161-173.
[1]丁立,张钧寿,龚明涛等.W/O/W型复乳剂的稳定性、生物分布和体外释放[J].药学进展,2000,1:12-16.
[2]汪自然,徐启勇,叶燕青.复乳法制备聚乳酸及其共聚物微球参数的研究进展[J].国际生物医学工程杂志,2006,29(4):238-242.
[3]Hart K,Lee K D,Gao Z G,et al.Preparation and evaluation of poly(L-lactic acid)microspherescontaining rhEGF for chronic gastric ulcer healing[J].Journal of Controlled Release,2001,75(3):259-269.
[4]Herrmann J,Bodmeier R.Somatostatin containing biodegradable microspheres prepared by a modified solvent evaporation method based on W/O/W-multiple emulsions[J].International Journal of Pharmaceutics,1995,126:129-138.
[5]Crotts G,Park T G.Preparation of porous and nonporous biodegradable polymeric hollow microspheres[J].Journal of Controlled Release,1995,35(2-3):91-105.
[6]Geiger S,Tokgoz S,Fructus A,et al.Kinetics of swelling-breakdown of a W/O/W multiple emulsion:possible mechanisms for the lipophilic surfactant effect[J].Journal of Controlled Release,1998,52(1-2):99-107.
[7]Yang Y Y,Chia H H,Chung T S.Effect of preparation temperature on the characteristics and release profiles of PLGA microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation[J].Journal of Controlled Release,2000,69(1):81-96.
[8]张建军,高缘,平其能.复乳化法制备聚乳酸微球的动态过程及其物理参数研究[J].中国药学杂志,2005,40(6):441-444.
[9]宋薇,马光辉,苏志国.复乳法制备大孔聚合物微球[J].过程工程学报,2007,7(5):1029-103.
[10]谭红香,叶建东.PLGA包埋硫酸庆大霉素缓释微球的制备及体外释放行[J].中国抗生素杂志,2007,32(11):682-684.
[11]Erden N,Celebi N.Factors influencing release of salbutamol sulphate from poly(lactide-co-glycolide)microspheres prepared by water-in-oil-in-water emulsion technique[J].International Journal of Pharmaceutics,1996,137(1):57-66.
[12]Yang Y Y,Chung T S,Bai X L,et al.Effect of preparation conditions on morphology and release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion method[J].Chemical Engineering Science,2000,5:2223-2236.
[13]Meng F T,Ma(3 H,Qiu W.W/O/W Double Emulsion Technique Using Ethyl Acetate as Organic Solvent:Effect of Its Diffusion Rate on the Characterization of Microparticles[J].Journal of Controlled Release,2003,91:407-416.
[14]Florence A T,Whitehill D.Some Features of Breakdown in Water-in-oil-in-water Multiple Emulsions[J].Journal Colloid Interface Sci.,1981,79:243-256.
[15]Sah H K,Toddywala R,Chien Y W.The influence of biodegradable microcapsule formulations on the controlled release of a protein[J].Journal of Controlled Release,1994,30:201-211.
[16]Herrmann J,Bodmeier R.The effect of particle microstructure on the somatostatin release from poly(lactide)microspheres prepared by a W/O/W solvent evaporation method[J].Journal of Controlled Release,1995,36(1-2):63-71.
[17]Ghadefi R,Sturesson C,Carlfors J.Effect of preparative parameters on the (D,L-lactide-co-glycolide)microspheres emulsion method characteristics of polymade by the double[J].International Journal of Pharmaceutics,1996,141(1-2):205-216.
[18]Ruana G,Feng S S,Li Q T.Effects of material hydrophobicity on physical properties of polymeric microspheres formed by double emulsion process[J].Journal of Controlled Release,2002,84(3):151-160.
[19]Ruana G,Feng S S.Preparation and characterization of poly(lactic acid)-poi(ethyleneglycol)-poly(lactic acid)(PLA-PEG-PLA)microspheres for controlled release of paclitaxel[J].Biomaterials,2003,24(27):5037-5044.
[20]王峰,涂家生,张钧寿,等.PLGA微球控释系统的突释及其控制[J].药学进展,2003,27(3):142-146.
[21]Wang J,Wang B M,Schwendeman S P.Characterization of the initial burst release of a model poptide from POly(d,l-lae-tide-co-glycofide)microspheres[J].Journal of Controlled Release,2002,82(2-3):289-307.
[22]Takenaga M,Yarnaguchi Y,Kitagawa A,et al.A novel sus-tained-release formulation of insulin with dramatic reduction in initial rapid release[J].Journal of Controlled Release,2002,79(1-3):81-91.
[23]Makoto M,Akiko K,Jun'ichi O,et al.Mechanism of drug release from poly(L-lactic acid)matrix containing acidic or neutral drugs[J].Journal of Controlled Release,1999,60(1-2):199-209.
[24]Urata T,Arimori K,Nakano M.Modification of release rates of eyelosporin A from polyl(L-laetic acid)mierospheres by fatty acid esters and in-vivo evaluation of the microspheres[J].Journal of Controlled Release,1999,58(2):133-141.